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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/60—Three or more oxygen or sulfur atoms
  • C07D239/62—Barbituric acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

• the present invention relates to new derivatives of the barbituric acid 5,5-bis-substituted.
• the elimination of the primary tumor by surgery is not always possible and in any case does not prevent the most metastasizing tumors, such as for example breast cancer or melanoma, to invade other target organs, which develop further secondary tumors after months or years from the surgical treatment. These secondary tumors are usually the main cause of death of the patient.
• cytotoxic drugs is now seen as a palliative and life-prolonging method rather than a curative method.
• a cronical treatment with a drug having low toxicity would be preferable while targeted to the control of the progression of the disease.
• An example of such therapy is the treatment of invasive breast cancer with tamoxifen.
• the matrix metalloproteinases (or metalloproteases), which are upregulated in the cancer cells, degrade the extracellular matrix and bring to the propagation of the tumor cells into the blood stream to reach the target organs where the metastasis develop. Moreover, they are associated with tumor growth and angiogenesis. Nevertheless, since different types of such proteases exist in the organism and are implicated in the regulation of vital functions, selected inhibition of certain combination of MMPs is desired, in order to avoid toxic side effects, especially in a chronical treatment.
• the present invention relates to compounds of the general formula (I): wherein:
• the present invention also encompasses enantiomers, racemates, diastereoisomers, tautomers of the compounds of formula (I) or mixtures thereof, as well as their salts with pharmaceutically acceptable acids or bases.
• halogen means an atom selected from chlorine, bromine, iodine or fluorine.
• cycloalkanes or aryl groups such as for example cylopropyl, cyclopentyl, cyclohexyl, decalinyl, phenyl or naphtalenyl groups,
• alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-hexyl, n-heptyl or n-octyl.
• Preferred examples of 5- or 6-membered heterocycles, optionally benzocondensed are pyrrolidine, piperidine, morpholine, tiomorpholine, piperazine, pyrane, oxadiazole, tiophene, furane, pyrazole, imidazole, thiazole, pyridine, pyrazine, pyrimidine, indole, indazole, quinoline, isoquinoline, benzopyrimidine, benzopyrazine, benzofurane, benzothiophene, benzothiazole, benzopyrane.
• lactams optionally benzocondensed
• lactams are pyrrolidinone, caprolactam, phtalimide, benzisothiazol-3(2H)one-1,1-dioxide, 2-imidazolinone, benzopyrimidin-2,4-dione, benzopyrimidin-4-one, 8-azaspiro[4,5]decane-7,9-dione, piperidine-2,3-dione.
• Preferred compounds of formula (I) are those in which n is 1, A is a R 1 or a -N(R 2 )-(CH 2 ) m -N(R 9 )-CO R 10 group and R is selected from a (C 6 -C 20 )alkyl, biphenyl, phenoxyphenyl or (C 1 -C 4 )alkoxyphenyl group. Particularly preferred are those in which m is 2 and R 2 is a (C 1 -C 4 )alkyl, phenyl or benzyl group.
• Another object of the present invention is to provide a method for the preparation of the compounds of formula (I).
• a further object of the present invention is the use of the compounds of formula (I) in the treatment of those diseases which are susceptible of treatment with inhibitors of the matrix metalloproteinases, as well as pharmaceutical compositions containing effective dosages of one or more compounds of formula (I) in admixture with suitable excipients and/or diluents.
• the compounds of formula (I) can be prepared according to the following multi-step process:
• Example of such a reaction can be found in Synthesis, 11 , 954 (1991), J. Het. Chem., 22(4) , 1009-10 (1985), Arch. Pharm., 318(12) , 1052-70 (1985). Helv. Chim. Acta. 70(1) , 262-70 (1987), Eur. J. Med. Chem., 24 , 421-6 (1989) and J. Ore. Chem.. 54 , 2428-32 (1989), which are herein incorporated by reference.
• the compounds of formula (II) are known compounds or can be prepared according to methodologies well known to the expert in the art. For example, the synthesis of 5-phenyl barbituric acid is reported in Acta Chim. Acad. Sci. Hung., 107 , 139-45 (1981). In general, they are prepared by reacting a 2-substituted malonic derivative of formula (VIII): in which R has the above meanings and R' is a hydrogen or (C 1 -C 4 )alkyl group, with urea in the presence of a strong base such as for example an alkaline methoxide or ethoxide, in a solvent and at temperatures ranging from room temperature and the reflux temperature of the solvent.
• a strong base such as for example an alkaline methoxide or ethoxide
• compounds of formula (IV) can be obtained by functionalizing an 1, ⁇ -diamine on the nitrogen atoms or by reacting an ⁇ -chloro- or bromo-amine with an other amine optionally in the presence of an excess of the same amine of another base.
• Compounds of formula (V) are aminoacids and can be natural or synthetic aminoacids.
• the acylsulfamide derivatives are obtained, for example, by reaction of a substituted sulfamide of formula R 3 R 4 N-SO 2 -NH(R 2 ) with the acyl chloride of the barbituric derivative, as described in J. Het. Chem., 15 , 221 (1978). J. Chem. Soc. Perk. Trans., 4 , 643-5 (1986) and Collect. Czechosl. Chem. Com., 49(4) , 840-51 (1984), which are herein incorporated by reference.
• Other synthesis of sulfamide derivatives are described in Ber. Dtsch. Chem. Ges., 100 , 2719 (1967), J. Med. Chem., 8 , 766 (1965). J. Org, Chem., 54(24) , 5824 (1989) and J. Med. Chem., 33 , 585-91 (1990), which are also incorporated by reference.
• the compounds of the present invention have been tested in a pharmacological "in vitro" test of inhibition of MMP8 (human neutrophil collagenase). Said test provides for the determination via fluorescence of the inhibition of the desradation of a fluorescent substrate (DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH 2 , M1855 Bachem) by means of the catalytic domain of MMP8.
• MMP8 human neutrophil collagenase
• % Inhibition 100 - (rel. unit/time with inhibitor /rel. unit/time control x 100).
• MMP-9 gelatinase 92 kD
• Table I shows the biological results for some representative compounds of the invention in comparison with the known matrix metalloproteinase inhibitor batimastat:
• the compounds of the present invention have also shown activity in a test of chemoinvasion.
• the Costar Transwell chambers for cell culture (diameter: 6.5 mm; pore size: 8 ⁇ m) are coated with 100 ⁇ l of Type IV collagen (diluted solution 50 ⁇ g/ml, then evaporation overnight). With the same procedure the chambers are coated with a second laver of Type IV collagen (100 ⁇ l of solution at concentration 50 ⁇ g/ml). Before use, the chambers are rinsed twice with sterile water and incubated for about 1 hour at 37°C in a serum-free medium (DMEM).
• DMEM serum-free medium
• the human fibrosarcoma HT1080 cells are harvested by trypsin-EDTA treatment, washed with DMEM + 10% FCS and incubated for at least 30 minutes at 37°C in the same medium. The cells are then washed with serum-free DMEM and resuspended in serum-free DMEM added with 0. 1% BSA (fraction V), counted and diluted to obtain a final density of 3x10 5 cell/ml.
• Preincubated inserts are aspirated to remove the serum-free medium.
• the lower compartment of the chambers is filled with 600 ⁇ l of DMEM + 20% FCS + 1% BSA (fraction V) + compound to test.
• 200 ⁇ l of cell suspension (6x 10 4 cells) containing the compound to test are added to the upper compartment and the chambers are incubated at 37°C under humid atmosphere with CO 2 . After first 24 hour incubation the media from both lower and upper compartments are replaced by fresh suspensions and the chambers are incubated for additional 24 hours.
• Incubated filters are then washed with PBS, the cells are fixed 15 min, in 4% paraformaldehyde, permeabilized in methanol (10 minutes. -20°C) and stained with May-Grunwald-Giemsa.
• Cells which adhere to the top of the filters are removed with a cotton swab, filters are detached from the bottom of the chambers and analyzed with microscope to determine the number of cells on the lower side of the filters.
• HT1080 cells which overexpress metalloproteinases, are able to degrade Type IV collagen and to migrate to the lower side of the filters.
• the activity of the metalloproteinases is partially or totally inhibited and the number of cells which migrate to the lower side of the filters is decreased.
• the result of the experiment is expressed as percent of inhibition of chemoinvasion in the experiment with the metalloproteinase inhibitor (0% of inhibition in the control experiment).
• the compounds of the invention in addition to their application in cancer therapy, may be used in the treatment of the conditions associated with the elevated or uncontrolled activity of the metzincins, as it is named the common family of zinc endopeptidases with high structural analogy which encompasses the MMPs, the astacins, the adamalysisns and the serralysisns.
• Examples of the diseases that can be treated with the compounds of the invention are inflammation, fibrosis, rheumatoid arthritis, osteoarthritis, atherosclerotic plaque rupture, aortic aneurism, heart failure, restenosis, septic arthritis, ulceration of the cornea, epidermic or gastric ulcerations, coronary thrombosis, proteinuria, pathological consequences of traumas, emphysema, multiple sclerosis, osteoporosis, periodontal disease or even as contraceptive agents.
• the compounds of the present invention can be administered in doses ranging from 0.01 mg to 0.4 g per kilogram of body weight daily.
• a preferred dosage regimen to obtain best results is that which provides for the use from about 1 mg to about 50 mg per kilogram of body weight daily, employing unitary doses so that to administer in 24 hours from about 70 mg to about 3.5 g of the active compound to a patient having approximately 70 kg of body weight.
• Such a dosage regimen may be adjusted to achieve the best therapeutical effect.
• doses may be administered taking into account the therapeutical situation of the patient.
• the active compound may be administered by oral, intravenous, intramuscular or subcutaneous route.
• compositions of the present invention contain therapeutical effective amounts of at least one compound of the invention in admixture with pharmaceutically compatible excipients.
• Oral compositions will generally include an inert diluent or an edible carrier. They can be included in gelatin capsules or compressed into tablets. Other oral administration forms are capsules, pills, elixirs, suspensions or syrups.
• the tablets, pills, capsules and similar compositions can contain the following ingredients (in addition to the active compound): a binder such as microcrysialline cellulose, tragacanth or gelatin: an excipient such as starch or lactose: a disintegratins agent such as alginic acid, primogel, maize starch and the like: a lubricant such as magnesium stearate: a fluidifier such as colloidal silicon dioxide: a sweetening agent such as sucrose or saccharine or a flavoring agent such as mint flavor, methyl salicylate or orange flavor.
• a binder such as microcrysialline cellulose, tragacanth or gelatin
• an excipient such as starch or lactose: a disintegratins agent such as alginic acid, primogel, maize starch and the like
• a lubricant such as magnesium stearate
• a fluidifier such as colloidal silicon dioxide
• the active ingredient can be included in solutions or suspensions, which can comprise in addition the following components: a sterile diluent such as water for injections, saline solution, oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents: antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulfite: chelatine agents such as ethylenediaminotetracetic acid: buffers such as acetates, citrates or phosphates and agents for adjusting the tonicity of the solution, such as sodium chloride or dextrose.
• a sterile diluent such as water for injections, saline solution, oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents
• antibacterial agents such as benzyl alcohol
• antioxidants such as ascorbic acid or sodium bisulfite
• chelatine agents such as ethylenediaminotetracetic acid
• buffers such as
• the solvent is evaporated and the resulting residue is dissolved in water (25 ml) and acidified with 6N hydrochloric acid until pH1.5-2 is reached.
• the acidic aqueous phase is extracted twice with ethyl acetate (2 x 25 ml) to remove some impurities, then is basified to pH 11 with 20% sodium hydroxide and further extracted twice with diethyl ether (2 x 50 ml).
• the pooled organic phases are dried over sodium sulfate and concentrated to dryness to give 1.367 g of the product as a clear oil which on standing solidifies.
• a suspension of 5 g of barbituric acid in 50 ml of water is heated until a compklete dissolution occurs, then it is added with 4.3 ml of benzaldheide.
• the mixture is refluxed for 1 hour, then the solid which separated is filtered, washed several times with water and dried under vacuum at 100°C. to give 8.17 g of the product, m.p. >258°C.
• a solution of sodium (0.32 g) in 30 ml of anhydrous ethanol is added with diethyl 2-naphtylmalonate (2 g) and successively with urea (0.63 g).
• a white solid precipitates which, after 30 minutes under stirring, is filtered and washed with water. The solid is dried overnight under vacuum at 40°C, to give 0.96 g of the product.
• a solution of sodium (0.322 g) in 40 ml of anhydrous ethanol is added with diethyl (4'-biphenyl)malonate (2.2 g) and successively with urea (0.63 g).
• the reaction mixture is refluxed for 3 hours 30 minutes, then it is cooled to room temperature and the solid is recovered by filtration.
• the solid which separates is kept 15 minutes under stirring, then it is filtered and dried under vacuum at 60°C. 1.1 g of the product are obtained. m.p. >240°C.
• reaction mixture is refluxed for 2 hours 30 minutes, then it is cooled to room temperature and the suspended solid is filtered.
• the solid is redissolved in 8 ml of water and the solution is acidified with 1 N hydrochloric acid.
• the solid which separates is recovered by filtration to give 0.165 g of the product. m.p. >240°C.
• a solution of sodium (0.46 g) in 10 of anhydrous ethanol is added with 3.35 ml of diethyl malonate in 3 ml of ethanol and successively with a solution of decylbromide (4.15 ml) in 3 ml of ethanol.
• the reaction mixture is refluxed for 4 hours, then the precipitate is filtered off and the filtrate is concentrated to dryness.
• the residue is redissolved in a saturated aqueous solution of sodium hydroeensulfate and it is extracted with ethyl acetate.
• the organic extract is dried over sodium sulfate and the solvent is evaporated off.
• the resulting residue is used as such in the successive reaction.
• step a) To a solution of diethyl decylmalonate of step a) in 40 ml of ethanol are added 2.72 g of sodium ethoxide and then 1.8 g of urea. The reaction mixture is refluxed for 2 hours, then the precipitate is filtered and redissolved in 40 ml of water. The resulting aqueous solution is acidified with 6 N hydrochloric acid. The solid which separates is recovered by filtration and dried under vacuum at 40°C overnight, to give 2.152 g of the product. m.p. 190°C
• the mixture is allowed to warm to room temperature and is stirred for 70 hours.
• reaction mixture is concentrated to a little volume and the residue is partitioned between 0.1 N hydrochloric acid (20 ml) and ethyl acetate (25 ml).
• the organic phase is washed with 20 ml of saturated aqueous solution of sodium chloride and dried over sodium sulfate. Removal of the solvent affords 130 mg of crude product, which is purified by column chromatography (SiO 2 , eluant: dichloromethane/ethyl acetate 75 : 25) to give 60 mg of pure product as white amorphous solid.
• 5-octyl-5-(carboxymethyl)barbituric acid (215 mg: example 2) is suspended in thionyl chloride (3 ml) and the mixture is refluxed for 1 hour. The resulting solution is concentrated to a small volume, diluted with anhydrous toluene and evaporated to dryness. The obtained residue is taken up in dichloromethane (2 ml) and to the resulting solution, kept under nitrogen atmosphere and cooled to 0°C. is added N-benzyl-N'-acetylethylenediamine (180 mg; preparation 1) in one portion and successively pyridine (0.5 ml).
• reaction mixture is stirred for 1.5 hours, then it is concentrated to a little volume and the residue is partitioned between 1N hydrochloric acid (3 ml) and diethyl ether (3 ml).
• a white solid separates from the mixture which is recovered by filtration and successively washed on the filter with water and ethyl acetate.
• the isolated precipitate is dissolved on warming in ethyl acetate (20 ml) and the resulting solution is dried over sodium sulfate and concentrated to dryness.
• the obtained residue is triturated with ethyl acetate at reflux to give 180 me of the product as white solid.
• TLC SiO 2 , eluant: chloroform/methanol 85 : 15]: detection u.v.

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